The possible involvement of mutation in the transformation process is being examined by two approaches. First, the pattern of stable alteration of the structure of cellular genes induced by treatment with chemical carcinogens was investigated by comparing the DNA sequences of four actin genes isolated from a human fibroblast line transformed by 4-nitro-quinoline-l-oxide (4NQ0) with those of normal genes. The results suggest that the most frequent alterations of DNA sequence, either induced by 4NQ0 treatment of arising spontaneously, and base substitution, one point mutation and, less frequently, one-base insertion or deletion. Secondly, the possibility that chemically-induced cell transformation results in genetic instability which increases the probability of neoplastic progression, was tested by comparing the mutation rates of normal diploid human fibroblasts and a chemically transformed human fibroblast line. When two genetic loci, i.e., the hypoxanthine-guanine phosphoribosyl transferase locus, a X-linked recessive locus, and the Na+-K+ ATPase locus, an autosomal codominant locus, were used, the mutation rates of the normal and transformed cells did not differ significantly. Thus, it was concluded that increased mutation rates do not necessarily occur following chemical transformation.